Heparanase is a mammalian endo-β-D-glucuronidase that specifically degrades heparan sulfate (HS) proteoglycans ubiquitously associated with cell surfaces and the extracellular matrix. Heparanase activity has been correlated and causally associated with the metastatic potential of tumor-derived cells, attributed to enhanced cell dissemination as a consequence of HS cleavage and remodeling of the ECM barrier. Similarly, heparanase activity is implicated in neovascularization, inflammation and autoimmunity, involving migration of vascular endothelial cells and activated cells of the immune system. Moreover, heparanase upregulation correlates with increased tumor vascularity and poor post-operative survival of cancer patients.
Despite earlier reports on the existence of several mammalian heparin/HS degrading endoglycosidases, cloning of the same gene by several groups indicates that mammalian cells express primarily a single dominant functional heparanase (Hulett et al., Nat. Med., 1999, 5: 803-809; Vlodaysky et al., Nat. Med., 1999, 5: 793-802).
As heparanase plays a critical role in fundamental biological phenomena, ranging from morphogenesis, development and homeostasis to inflammation, angiogenesis and cancer metastasis, there is a need in the art for animal models, which allow studying heparanase in vivo. US patent publication US 2002/0194625 discloses transgenic mice over-expressing human heparanase and uses thereof in studying pathological processes such as tumorigenesis. International patent publication WO 2004/006949 discloses the use of heparanase over-expressing transgenic mice as a model system for testing the role of heparanase in various aspects of hair growth.
Given the important and multifaceted roles of heparanase, animals lacking heparanase activity would provide valuable tools for elaborating the roles of heparanase. Despite of the recognized need in the art and several attempts to create heparanase knockout animals, such animals are not currently available. International patent publication WO 2005/118808 discloses silencing of heparanase activity in cells by small interfering RNA (siRNA) technique. Unfortunately, siRNA technique is not suitable for creating stable knockout mammal lines nor silencing heparanase activity completely.
Thus, animals lacking heparanase activity are still needed.